Our immediate objective is to focus on the enzyme propionyl-CoA carboxylase and the metabolic consequences of a mutation in this enzyme in humans with propionic acidemia. We are working to attempt to develop a strategy for metabolic rescue of organisms with this type of mutation. The strategy involves recruitment of alternate pathways of propionyl-CoA metabolism, and is being pursued initially by biochemical genetics approaches in a bacterial model system. Attempts will be made to identify gratuitous inducers of alternate propionate pathways; such gratuitous inducers will be tested for their ability to rescue propionyl-CoA carboxylase mutants under metabolite stress due to accumulated intracellular propionyl-CoA.